The enzyme HMG CoA reductase catalyzes conversion of HMG CoA to mevalonate, a rate-limiting step in synthesis of cholesterol and essential nonsterol isoprenoids. Reductase is anchored to endoplasmic reticulum (ER) membranes through an N-terminal domain that contains eight membrane-spanning helices; the C- terminal domain projects into the cytosol and exerts catalytic activity. Accelerated ER-associated degradation (ERAD), one of several mechanisms for feedback control of reductase, results from sterol-induced binding of reductase to ER membrane proteins called Insig-1 and Insig-2. Ubiquitination of reductase by Insig-associated ubiquitin ligases marks the enzyme for retrotranslocation across ER membranes and dislocation into the cytosol for proteasomal degradation. These postubiquitination steps are modulated by the nonsterol isoprenoid geranylgeraniol through a completely unknown mechanism. In preliminary studies, we find that sterols also trigger binding of reductase to UbiA prenyltransferase domain containing protein-1 (UBIAD1), which catalyzes geranylgeranylation of bacterial and plant vitamin K derivatives to produce menaquinone-4 (MK-4). Mutations in UBIAD1 cause a rare autosomal dominant eye disease called Schnyder corneal dystrophy (SCD), which is characterized by progressive accumulation of cholesterol in the cornea. Sterol-induced binding of reductase to UBIAD1 is inhibited by geranylgeraniol and RNA interference studies reveal that reductase-UBIAD1 binding leads to Insig recruitment and ERAD of reductase. Thus, we hypothesize that 1) UBIAD1 mediates the sterol-sensing reaction required for reductase-Insig binding; and 2) geranylgeraniol-mediated displacement of UBIAD1 is required for initiation of postubiquitination steps in reductase ERAD. To appraise these hypotheses, we propose three Specific Aims: 1) delineate mechanisms by which UBIAD1 mediates sterol-accelerated ERAD of reductase; 2) explore mechanism through which sterols modulate function of UBIAD1; and 3) determine the role of UBIAD1 in ERAD of reductase and regulation of cholesterol homeostasis in whole animals. Collectively, these studies will provide key information regarding the removal of polytopic proteins from ER membranes for proteasomal degradation. In addition, these studies have significant clinical implications. Reductase is the target of statins, widely prescribed drugs that lower plasma LDL-cholesterol and reduce the incidence of cardiovascular disease. Statins trigger responses that cause accumulation of reductase, which blunts their clinical effects. Part of this increase results from slowed ERAD of reductase. Thus, elucidating mechanisms for reductase ERAD holds promise for development of new therapies that increase the effectiveness of statins and ultimately reduce the incidence of heart attacks. Moreover, insight into mechanisms for reductase ERAD may lead to therapeutic interventions that retard or prevent corneal accumulation of cholesterol associated with SCD.